EP2114407A1 - Use of sodium blockers for an early therapy of obstructive lung diseases - Google Patents
Use of sodium blockers for an early therapy of obstructive lung diseasesInfo
- Publication number
- EP2114407A1 EP2114407A1 EP08700996A EP08700996A EP2114407A1 EP 2114407 A1 EP2114407 A1 EP 2114407A1 EP 08700996 A EP08700996 A EP 08700996A EP 08700996 A EP08700996 A EP 08700996A EP 2114407 A1 EP2114407 A1 EP 2114407A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amiloride
- mice
- lung disease
- treated
- transgenic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Definitions
- the present invention relates to a blocker of sodium channels in cell membranes, particularly in membranes of epithelial cells of organs belonging to the respiratory tract to be used as the pharmaceutically active ingredient in a medicament for treating an obstructive lung disease in a patient.
- CF cystic fibrosis 1 neonatal chronic lung disease (CLD), also known as bronchopulmonary dysplasia (BPD), asthma bronchiale and chronic bronchitis (also known as chronic obstructive pulmonar disease; COPD) belong to the most common chronic diseases in Western Europe and North America. While CF is the most common fatal hereditary disease in the white population, CLD is a frequent health problem of premature infants. Asthma bronchiale is one of the most common chronic diseases of children and asults. Cigarette smoke induced COPD is currently the fourth leading cause of death worlwide.
- CLD cystic fibrosis 1 neonatal chronic lung disease
- BPD bronchopulmonary dysplasia
- COPD chronic obstructive pulmonar disease
- COPD chronic obstructive pulmonar disease
- the problem underlying the present invention is to provide a new method for a successful in vivo therapy of obstructive lung diseases using sodium channel blockers.
- the present invention relates to the use of at least one sodium channel blocker as a pharmaceutically active ingredient of a medicament for treating an obstructive lung disease in a susceptible patient prior to having substantial mucus obstruction or secondary, disease related changes of the lung. Therefore, in one embodiment the present invention relates to the use of at least one sodium channel blocker as a pharmaceutically active ingredient of a medicament for an early therapy of an obstructive lung disease in a patient, wherein the early therapy is carried out in an early phase of the disease characterized by the lack of any substantial mucus obstruction or secondary, disease related changes of the lung.
- the sodium channel to be blocked may be any sodium channel in cell membranes, particularly in membranes of epithelial cells of organs belonging to the respiratory tract.
- the organ of the respiratory tract may be for example the trachea or the lung including bronchi, bronchioles, and alveoli.
- the sodium channels to be blocked are situated in membranes of epithelial cells of the lung.
- medium as used herein relates to any pharmaceutical composition comprising at least one sodium channel blocker in a pharmaceutically effective amount.
- the medicament may be administered by any administration route known in the art being suitable for delivering a medicament to the epithelium of an organ belonging to the respiratory tract.
- the route of administration does not exhibit particular limitations and includes for example inhalation, e.g. intrapulmonal, or nasal administration, systemic administration, e.g. by oral or intravenous route, and topic application, e.g. as an ointment.
- the medicament may be administered in any form known in the art, e.g. as a liquid, a powder, an aerosol, a capsule, or a tablet.
- the medicament is administered by an intrapulmonal application as an aerosol.
- the medicament according to the present invention may be for example inhaled, e.g. by using special devices or nebulizers, which administer the medicament in a fine spray that the patient breathes in.
- suitable inhalers which may be used for administering the medicament, like e.g. a metered-dose inhaler (MDI), which allows precise doses to be delivered directly to the lungs, are known to those skilled in the art.
- MDI metered-dose inhaler
- Such inhalers may use for example ozone-depleting chlorofluorocarbons or hydrofluoroalkane as propellants, but alternative delivery methods and propellants useful for delivering the medicament, like e.g. dry powder inhalers (DPIs), may also be used.
- DPIs dry powder inhalers
- lung therapy relates to a therapy that is initiated in a susceptible individual prior to the development of a lung disease (i.e. preventive) or in an early stage of an obstructive lung disease.
- This may be a preventive treatment that is initiated in a susceptible individual before the onset of a lung disease or a therapy for the treatment of an early stage of an obstructive lung disease, characterized e.g. by no progressed lung disease like mucus obstruction and no secondary changes of the lung, like e.g. airway remodelling, goblet cell metaplasia, chronic inflammation of the respiratory tract or emphysema, which may be evidenced e.g. by standard diagnostic tests including pulmonary function testing, pulmonary imaging, bronchoscopy with bronchoalveolar lavage.
- CF is an inherited multiorgan disease caused by mutations in the CFTR gene. Lungs are normal at birth and the disease typically presents with gastrointestinal symptoms like meconium ileus, malabsorption and maldigestion due to pancreatic insufficiency, and failure to growth, i.e. the clinical diagnosis can often be established and confirmed by standard laboratory tests like sweat test or genetic testing in infancy prior to the onset of lung disease. Some patients are already identified before birth by prenatal screening for CFTR mutations. Further, neonatal CF screening programmes are currently being established in many countries that will allow to identify CF patients in the first weeks of life. Taken together, the majority of CF patients in the Western world are identified before the onset of chronic lung disease.
- Neonatal CLD is caused by premature birth, i.e. patients at risk are readily identified and treatment can be commenced right after birth, i.e. before lung disease has developed.
- Asthma is an episodic, recurrent disease characterized by reversible airway obstruction caused by various triggers including viral infections, allergens, physical exercise, or cold air.
- various triggers including viral infections, allergens, physical exercise, or cold air.
- acute and recurrent episodes with reversible airflow obstruction due to mucus obstruction, goblet cell metaplasia, airway inflammation and related smooth muscle contraction alternate with symptom free episodes with no mucus obstruction, goblet cell metaplasia or inflammation in the absence of the trigger.
- "preventive or early therapy” could be commenced in a symptom free interval and preferably prevent or ameliorate the next asthma attack.
- a sodium channel blocker may be any molecule that is able to substantially decrease the ability of a sodium channel to transport sodium ions from the extracellular side of a cell membrane into the intracellular side of a cell membrane.
- the sodium channel blocker is selected from the group consisting of amiloride, amiloride analogs, P2Y2-receptor agonists such as nucleotides, like e.g. ATP or UTP, or long-acting synthetic compounds like nucleotide analogs (e.g. Denufosol), and protease inhibitors, including e.g. aprotinin or BAY 39-9437 (a recombinant Kunitz-type serine protease inhibitor) or derivatives thereof.
- P2Y2-receptor agonists such as nucleotides, like e.g. ATP or UTP, or long-acting synthetic compounds like nucleotide analogs (e.g. Denufosol)
- protease inhibitors including e.g. aprotinin or BAY 39-9437 (a recombinant Kunitz-type serine protease inhibitor) or derivatives thereof.
- the sodium channel blocker is amiloride (3,5-Diamino-N-(aminoiminomethyl)-6-chloro-pyrazinecarboxamide) or a derivative thereof.
- the term "derivative thereof” as used herein includes any derivative of a sodium channel blocker having substantially the same functional, such as biological and/or pharmacological, properties as the non- dehvatized sodium channel blocker, i.e. to effectively block sodium channels.
- the sodium channel blocker is used in a pharmaceutically effective amount.
- the sodium channel blocker is used in a amount ranging from about 0.1 mg/kg body weight to about 10 mg/kg body weight.
- amiloride is used in a amount ranging from about 0.3 mg/kg body weight to about 1 mg/kg body weight.
- a P2Y2-receptor agonist is used in a amount ranging from about 1 mg/kg body weight to about 2 mg/kg body weight.
- a protease inhibitor is used in a amount ranging from about 0.3 mg/kg body weight to about 1 mg/kg body weight.
- obstructive lung disease as used herein relates to a disease characterized by airflow limitation in the lung that develops over time.
- the obstructive lung disease according to the present invention may be associated with breathing-related symptoms, like e.g. cough, spitting or coughing mucus (expectoration), breathlessness upon exertion, progressive reduction in the ability to exhale, progressive shortness of breath, frequently accompanied by a phlegm-producing cough, with episodes of wheezing, irritation of the nose and throat, chest tightness or pain or a nonproductive cough.
- breathing-related symptoms like e.g. cough, spitting or coughing mucus (expectoration), breathlessness upon exertion, progressive reduction in the ability to exhale, progressive shortness of breath, frequently accompanied by a phlegm-producing cough, with episodes of wheezing, irritation of the nose and throat, chest tightness or pain or a nonproductive cough.
- breathing-related symptoms like e.g. cough, spi
- Examples of the obstructive lung disease according to the present invention are acute bronchitis which is usually caused by a virus and in most cases is self- limiting but can later develop either chronic bronchitis or asthma, and asthma which is characterized by attacks of coughing, wheezing, and shortness of breath (dyspnea).
- the obstructive lung disease is a chronic obstructive lung disease.
- An example of such a chronic obstructive lung disease is chronic bronchitis (COPD) being characterized by chronic cough and sputum production, intermittent wheezing with variable degrees of shortness of breath on exertion.
- COPD chronic bronchitis
- Other examples of chronic obstructive lung diseases are cystic fibrosis (CF) characterized by an increased transport of sodium across the respiratory tract lining which results in the dehydration of the liquid that lines the respiratory tract surface and neonatal chronic lung disease (CLD).
- the obstructive lung disease is selected from the group consisting of cystic fibrosis (CF), neonatal chronic lung disease (CLD), asthma bronchiale, and chronic bronchitis.
- CF cystic fibrosis
- CLD neonatal chronic lung disease
- asthma bronchiale chronic bronchitis
- chronic bronchitis chronic bronchitis.
- the obstructive lung disease is CF.
- treatment relates to the prevention and/or eradication or amelioration of disease related symptoms and/or disease related disorders.
- Obstructive lung diseases are often accompanied by pulmonal mortality, chronic inflammation of the respiratory tract, like e.g. pulmonal inflammation, mucus obstruction, resulting from secreted mucus, a viscous fluid composed primarily of highly glycosylated proteins called mucius suspended in a solution of electrolytes.
- obstructive lung diseases are goblet cell hyperplasia, goblet cell metaplasia being an important morphological feature in the respiratory tract of patients with chronic respiratory tract diseases, and emphysema which is a progressive destructive lung disease in which the walls between the alveoli in the lungs are damaged.
- a preferred embodiment of the present invention is a use of at least one sodium channel blocker in the manufacture of a medicament for an early therapy of an obstructive lung disease as described above, wherein at least one disorder selected from the group consisting of pulmonal mortality, pulmonal inflammation, mucus obstruction, goblet cell metaplasia, cellular necrosis of epithelial cells, and emphysema is reduced in the patient, e.g. when compared to patients not being treated with a sodium channel blocker according to the present invention.
- pulmonary function tests like e.g. spirometry employing a spirometer, an instrument that measures the air taken into and exhaled from the lungs, or the testing of arterial blood gas by determining the amount of oxygen and carbon dioxide in the blood, wherein low oxygen (hypoxia) and high carbon dioxide (hypercapnia) levels are often indicative of chronic bronchitis and emphysema.
- DLCO lung carbon monoxide diffusing capacity
- imaging tests like e.g. chest x-rays or computed tomography (CT) scans, and tests for the protective enzyme, alpha 1 -antiprotease (ATT or antitrypsin) which is often deficient in patients having an obstructive lung disease, and bronchoalveolar lavage for determination of inflammatory cells and pro-inflammatory cytokines in the lung may be employed.
- CT computed tomography
- the early therapy of an obstructive lung disease in a patient by use of a sodium channel blocker as described above can also be combined with any therapy known in the art for the therapy of an obstructive lung disease.
- the present invention also relates to the use of at least one sodium channel blocker in the manufacture of a medicament which may also contain further active agents like e.g.
- anticholinergic agents which relax the bronchial muscles and act as a bronchodilator when inhaled
- beta2 agonists being bronchodilators
- theophylline which acts by opening the respiratory tract, improving exchange of gases, reducing shortness of breath, improving mucus clearance, and stimulating the process of breathing
- corticosteroids being anti-inflammatory drugs
- osmotically active agents including hypertonic saline or mannitol that improve airway surface hydration by their osmotic action.
- patient does not underly any specific limitation and includes mammals.
- the patient is a human.
- the present invention further relates to a method of treating a patient having an obstructive lung disease as defined above with at least one sodium channel blocker as defined above, wherein the sodium channel blocker is administered in an early therapy as defined above.
- Figure 1 shows that early amiloride treatment (started on the first day of life and continued for 14 days) significantly improved survival of ⁇ ENaC-transgenic mice compared to vehicle treated ⁇ ENaC-transgenic littermates.
- H 2 O was used as vehicle in all experiments.
- n 35-48 mice per group.
- P 0.004.
- Figure 2 shows that late amiloride treatment (started on postnatal day 5 and continued for 14 days) had no effect on survival of ⁇ ENaC-transgenic mice compared to vehicle treated ⁇ ENaC-transgenic littermates.
- Wt wild-type
- tg ⁇ ENaC-transgenic.
- n 17-34 mice per group.
- FIG. 5 shows that BAL macrophages are activated ('foam cells') in vehicle treated ⁇ ENaC transgenic mice compared to wild-type littermates.
- Figure 6 shows that early amiloride treatment (started on first day of life and continued for 14 days) reduced severity of airway mucus plugging in ⁇ ENaC- transgenic mice (right panel) compared to vehicle (H 2 O) treated ⁇ ENaC- transgenic littermates (middle panel).
- Representative for n 16-34 mice per group.
- Figure 10 shows that preventive amiloride therapy reduces mortality, airway mucus obstruction and mucus hypersecretion in Scnn 7/>transgenic mice
- (a-e) Effect of preventive amiloride treatment, administered from the first day of life for a period of 2 weeks on survival (a), airway mucus content (b,c), goblet cell counts (d), and epithelial height in Scnn 7£>-transgenic (Scnn Ib-Tg) mice and wild-type (WT) littermates.
- (a) Survival curves for Scnn 1 / ⁇ -transgenic and wild- type mice treated with amiloride or vehicle alone; n 46-86 mice for each group.
- Figure 11 shows that late amiloride treatment in Scnn 7/>transgenic mice with established chronic obstructive lung disease has no effects on airway mucus obstruction, goblet cell metaplasia and pulmonary mortality
- (b) Mucus content was determined by measuring the volume density of AB-PAS positive material in proximal and distal main axial airways.
- Figure 12 shows that preventive, but not late amiloride therapy reduces airway inflammation in Scnn 7/>transgenic mice,
- (a-d) Effect of preventive treatment with amiloride or vehicle alone, administered from the first day of life for a period of 2 weeks, on inflammatory cell counts (a), concentration of the TH2 cytokine IL-13 (b), macrophage size (c) and macrophage morphology (d) in BAL from Scnn 7/>transgenic (Scnn Ib-Tg) mice and wildtype (WT) littermates.
- BAL cell counts; n 27-40 mice for each group. * , P ⁇ 0.05 compared with vehicle-treated wild-type. ** P ⁇ 0.001 compared with vehicle-treated wild-type.
- n 27-40 mice for each group, (e-j). Effect of late amiloride treatment, administered from the age of 5 days (e,g,i) or 4 weeks (f,h,j) for a period of 2 weeks, on cell counts (e,f), macrophage size (g,h), and IL-13 concentrations in BAL (i,j) from Scnn / ⁇ transgenic and wild- type mice.
- BAL cell 22 counts after treatment with intranasal amiloride or vehicle from the age of 5 days (e) or 4 weeks (f); n 13-34 mice for each group.
- Figure 13 shows that preventive amiloride therapy reduces airway epithelial necrosis in Scnn 7i>transgenic mice.
- (a,b) Effect of preventive amiloride treatment, administered from the first day of life for a period of 3 days on airway histology (a), and numbers of degenerative airway epithelial cells (b) in Scnnib- transgenic (Scnn1b-Tg) mice and wild-type (WT) littermates.
- n 7-12 mice for each group
- P 0.001 compared with vehicle-treated wild-type, t, P ⁇ 0.001 compared with vehicle- treated Scnn 7/>transgenic.
- the present invention advantageously provides a therapy for the successful treatment of obstructive lung diseases by applying a specific sodium channel blocker like amiloride or a derivative thereof in a living organism as an early therapy.
- the obstructive lung disease can be cured and disorders associated with said disease like e.g. pulmonal mortality, pulmonal inflammation, mucus obstruction, goblet cell metaplasia, and emphysema can be reduced.
- a preventive sodium channel blocker therapy protects epithelial cells from necrosis and, thus, reduces a strong stimulus for airway inflammation.
- the ⁇ -ENaC transgenic mouse has been used as an animal model for chronic obstructive lung diseases of humans to test, whether chronic obstructive lung disease can be treated successfully in a living organism by an early therapy with a sodium channel blocker, i.e. by starting treatment before the development of mucus obstruction and secondary changes of the lung occur. Similar to humans with chronic obstructive lung diseases including CF, CLD, asthma and COPD, the lungs of ⁇ -ENaC transgenic mice are normal at birth. Subsequently, ⁇ -ENaC transgenic mice develop a spontaneous lung disease that has great similarities to said chronic obstructive lung diseases in humans.
- ⁇ -ENaC transgenic mice At 5 days of age, ⁇ -ENaC transgenic mice have already developed significant mucus obstruction and airway inflammation that causes death due to respiratory failure in -50% of ⁇ -ENaC transgenic mice in the first 2 weeks of live. For this reason, we treated ⁇ -ENaC transgenic mice either from the first day of their lives, i.e. from a date, wherein there were no changes of the lung, or from their fifth day of their lives, i.e. from a date at which mucus obstructions and inflammation of the respiratory tract already existed, with an intrapulmonal application of amiloride.
- amiloride-treated mice received concomitant subcutaneous (s.c.) injections with isotonic sodium chloride solution (NaCI 0.9%).
- mice were monitored daily, and deceased mice were genotyped and mortality curves constructed for all treatment groups. At the end of the 2 week treatment cycle, surviving mice were euthanized, and lungs evaluated for several independent clinically relevant outcome measures, including bronchoalveolar lavage to determine therapeutic effects on pulmonary inflammatory cell counts; histopathology, morphometry and lung volume measurements determine effects on mucus obstruction, goblet cell metaplasia and emphysema.
- outcome measures including bronchoalveolar lavage to determine therapeutic effects on pulmonary inflammatory cell counts; histopathology, morphometry and lung volume measurements determine effects on mucus obstruction, goblet cell metaplasia and emphysema.
- Amiloride treatment Amiloride hydrochloride (Sigma) was dissolved in sterile distilled water (ddhteO). Newborn, 5-day, and 4-week-old Scnn 7fc>-transgenic mice and wild-type littermates were treated by intranasal instillation of amiloride (10 mmol/l; 1 ⁇ l/g body weight; 3 times per day) or vehicle (ddhteO) alone for a period of 13-14 days. Pulmonary deposition studies in newborn mice demonstrated that -4% of the amiloride dose delivered by intranasal instillation was deposited into the lungs.
- amiloride treatment growth and survival were monitored, and deficits in body mass observed in amiloride-treated mice were replaced by subcutaneous injections of isotonic saline (NaCI 0.9%). 12 hours after the last treatment, BAL was performed, lungs were removed for histology, morphometry and transcript expression studies, and serum and urine were sampled to determine renal effects of absorbed amiloride on Na+ and K+ concentrations. Endpoint studies were performed by an investigator blinded to the genotype and the treatment of the mice.
- BAL cell counts and cytokine measurements were deeply anesthetized via intraperitoneal injection of a combination of ketamin/xylazin (120 mg/kg and 16 mg/kg, respectively), the trachea cannulated, and lungs lavaged with PBS. Samples were centrifuged and the cell-free bronchoalveolar lavage (BAL) fluid was stored at -80 0 C. Total cell counts were determined and differential cell counts performed on cytospin preparations, as previously described (Mall.M., Grubb.B.R., Harkema.J.R., O'Neal.W.K. & Boucher.R.C.
- Macrophage size was determined by measuring their surface area using Analysis B image analysis software (Olympus). IL- 13 concentrations were measured in BAL using ELISA (R&D Systems) according to manufacturer's instructions.
- mice Histology and airway morphometry. Anesthetized mice were killed by exsanguination. Lungs were removed through a median sternotomy, fixed in 4% buffered formalin, and embedded in paraffin. Lungs were sectioned at the level of the proximal intra-pulmonary main axial airway near the hilus, and at the distal intra-pulmonary axial airway, at 1000 ⁇ m (2 to 3 week old mice) or 1500 ⁇ m (6 week old mice) distal to the hilus. Sections were cut at 5 ⁇ m and stained with hematoxylin and eosin (H&E) or alcian blue periodic acid-Schiff (AB-PAS).
- H&E hematoxylin and eosin
- ABS alcian blue periodic acid-Schiff
- the volume density of the airway epithelium was determined as a measure of epithelial height.
- Goblet cells were identified by the presence of intra-cellular AB-PAS positive material, and degenerative airway epithelial cells were identified by morphologic criteria (i.e. cell swelling with cytoplasmic vacuolization). Numeric cell densities were quantitated by counting epithelial cells per mm of the basement membrane. All morphometric measurements were performed by an investigator blinded to the genotype and the treatment of the mice.
- Real-time RT-PCR Lungs were stored in RNAIater (Applied Biosystems) and total RNA was isolated using Trizol reagent (Invitrogen). RNA integrity was verified by agarose gel electrophoresis, and cDNA obtained by reverse transcription of 2 ⁇ g of total RNA (Superscript III RT; Invitrogen).
- Real-time PCR for Muc ⁇ ac, Gob5, Scnnib and Gapdh was performed on an Applied Biosystems 7500 Real Time PCR System using TaqMan universal PCR master mix and inventored TaqMan gene expression assays according to the manufacturer's instructions (Applied Biosystems). Relative fold changes in target gene expression were calculated from the efficiency of the PCR reaction and the crossing point deviation between samples from the four treatment groups, and determined by normalization to expression of the reference gene Gapdh, as previously described.
- the lungs of Scnn 7/>transgenic mice are structurally normal at birth, but develop central airway mucus obstruction in the first days of life.
- amiloride administration to Scnn 7_>transgenic mice was started on the first day of life, i.e. prior to the onset of lung disease, utilizing a protocol of intranasal administration of amiloride (10 mmol/l; 1 ⁇ l/g body weight) or vehicle (ddhteO) alone 3 times daily for a period of 2 weeks. Wild-type littermates were treated with the same protocol to assess for pulmonary toxicity of amiloride therapy. Renal effects of absorbed amiloride were determined by measuring Na + and K + concentrations in serum and urine and weight loss due to diuresis. Volume losses were replaced by subcutaneous injections of isotonic saline (NaCI 0.9%).
- amiloride therapy was still effective when treatment was started at the age of 5 days, i.e. after the onset of proximal mucus plug formation, but prior to the establishment of chronic lung disease in Scnnib- transgenic mice.
- initiating amiloride treatment in mice that were alive at the age of 5 days for a period of 2 weeks failed to reduce mortality in amiloride- treated versus vehicle treated Scnn 76-transgenic mice (Fig. 11d).
- initiating amiloride treatment at the age of 5 days had no effect on airway mucus obstruction or goblet cell metaplasia in Scnn7/>transgenic mice (Fig. 11e,f).
- Neonatal (but not 4 week old) Scnn 7/>transgenic mice develop airway epithelial hypoxia and epithelial cell necrosis, likely resulting from combined effects of increased epithelial 02 consumption due to Na+ hyperabsorption and decreased 02 delivery due to airway mucus plugging.
- amiloride inhalation therapy in CF patients was mainly attributed to (i) insufficient pulmonary delivery of amiloride due to limited solubility restricting the amount that could be delivered by a nebulizer, (ii) limited potency, and (iii) limited half-life of amiloride on airway surfaces.
- Our findings showing that amiloride can be delivered to the lung in therapeutically active quantities prior to the onset of lung disease suggest that airway mucus obstruction and/or airway remodeling were contributing factors to the absence of therapeutic benefits in older Scnn 7 ⁇ transgenic mice and CF patients with established lung disease.
- amiloride is inexpensive, readily available and has been in clinical use as a diuretic for many years, and that together with a widespread implementation of CF newborn screening programs, and recent improvements in nebulizer technology allowing enhanced aerosol delivery to the neonatal and infant human lung, this facilitates the translation of preventive amiloride therapy according to the present invention for chronic obstructive lung disease from mice to the clinic.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08700996A EP2114407B1 (en) | 2007-01-08 | 2008-01-07 | Use of sodium blockers for an early therapy of obstructive lung diseases |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07000267A EP1941883A1 (en) | 2007-01-08 | 2007-01-08 | Use of sodium blockers for an early therapy of obstructive lung diseases |
PCT/EP2008/000051 WO2008083942A1 (en) | 2007-01-08 | 2008-01-07 | Use of sodium blockers for an early therapy of obstructive lung diseases |
EP08700996A EP2114407B1 (en) | 2007-01-08 | 2008-01-07 | Use of sodium blockers for an early therapy of obstructive lung diseases |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2114407A1 true EP2114407A1 (en) | 2009-11-11 |
EP2114407B1 EP2114407B1 (en) | 2011-04-06 |
Family
ID=38093414
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07000267A Withdrawn EP1941883A1 (en) | 2007-01-08 | 2007-01-08 | Use of sodium blockers for an early therapy of obstructive lung diseases |
EP08700996A Not-in-force EP2114407B1 (en) | 2007-01-08 | 2008-01-07 | Use of sodium blockers for an early therapy of obstructive lung diseases |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07000267A Withdrawn EP1941883A1 (en) | 2007-01-08 | 2007-01-08 | Use of sodium blockers for an early therapy of obstructive lung diseases |
Country Status (5)
Country | Link |
---|---|
US (1) | US20090312348A1 (en) |
EP (2) | EP1941883A1 (en) |
AT (1) | ATE504301T1 (en) |
DE (1) | DE602008006024D1 (en) |
WO (1) | WO2008083942A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201922239A (en) * | 2017-10-04 | 2019-06-16 | 英商尼姆生物技術有限公司 | Pharmaceutical compositions and uses thereof |
US20240307293A1 (en) * | 2021-07-01 | 2024-09-19 | AquaPass Ltd. | Methods and devices for modulating electrolyte excretion |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4501729A (en) * | 1982-12-13 | 1985-02-26 | Research Corporation | Aerosolized amiloride treatment of retained pulmonary secretions |
AU654979B2 (en) * | 1990-10-05 | 1994-12-01 | University Of North Carolina At Chapel Hill, The | Method of administering amiloride |
CA2332540A1 (en) * | 1998-05-22 | 1999-12-02 | Benjamin R. Yerxa | Therapeutic dinucleotide and derivatives |
CA2575670A1 (en) * | 2004-08-18 | 2006-03-02 | Michael R. Johnson | Aliphatic amide & ester pyrazinoylguanidine sodium channel blockers |
-
2007
- 2007-01-08 EP EP07000267A patent/EP1941883A1/en not_active Withdrawn
-
2008
- 2008-01-07 US US12/522,369 patent/US20090312348A1/en not_active Abandoned
- 2008-01-07 WO PCT/EP2008/000051 patent/WO2008083942A1/en active Application Filing
- 2008-01-07 AT AT08700996T patent/ATE504301T1/en not_active IP Right Cessation
- 2008-01-07 DE DE602008006024T patent/DE602008006024D1/en active Active
- 2008-01-07 EP EP08700996A patent/EP2114407B1/en not_active Not-in-force
Non-Patent Citations (1)
Title |
---|
See references of WO2008083942A1 * |
Also Published As
Publication number | Publication date |
---|---|
ATE504301T1 (en) | 2011-04-15 |
EP2114407B1 (en) | 2011-04-06 |
US20090312348A1 (en) | 2009-12-17 |
DE602008006024D1 (en) | 2011-05-19 |
EP1941883A1 (en) | 2008-07-09 |
WO2008083942A1 (en) | 2008-07-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Wanner et al. | Mucociliary clearance in the airways. | |
KR100518066B1 (en) | Method of treating bronchitis with uridine triphosphates and related compounds | |
ES2315382T3 (en) | PROCEDURE FOR THE TREATMENT OF BRONCHIAL CONSTRICTION AND BRONCHOSPASM. | |
EP2114407B1 (en) | Use of sodium blockers for an early therapy of obstructive lung diseases | |
JPWO2005004914A1 (en) | PHARMACEUTICAL COMPOSITION FOR TREATMENT AND PREVENTION OF RESPIRATORY DISEASE CONTAINING NF-κB DECOY AND METHOD OF USING THE SAME | |
US20070254928A1 (en) | Use of Roflumilast for the Prophylaxis or Treatment of Emphysema | |
JP6013450B2 (en) | Chronic obstructive pulmonary disease improving agent | |
Rochat et al. | Gene therapy for cystic fibrosis by means of aerosol | |
Christensen et al. | Acid-induced secretory cell metaplasia in hamster bronchi | |
JP7366074B2 (en) | 3”,5”-dialkosybenzoyl-3’-amino-3’-deoxyadenosine-5’-triphosphate and its pharmaceutical uses | |
Habler et al. | Eight hours' inhalation of prostacyclin (PGl 2) in healthy lambs: Effects on tracheal, bronchial, and alveolar morphology | |
US20220168297A1 (en) | Methods and compositions for treating chronic obstructive pulmonary disease, asthma, pneumonia, bronchitis, cystic fibrosis, pulmonary edema, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary arterial hypertension | |
Foster | Mucus hypersecretion and mucus clearance in cough | |
US20090215868A1 (en) | Therapeutic Medicament for Chronic Obstructive Pulmonary Disease (COPD), Cystic Fibrosis, and Pulmonary Hypertension | |
CN111454366B (en) | Fusion protein and application thereof | |
JP6021952B2 (en) | Treatment of chronic obstructive pulmonary disease | |
CN108530348B (en) | Medicine for treating chronic obstructive pulmonary disease and preparation method thereof | |
WO1993001826A1 (en) | Method of treating asthma | |
US20180296559A1 (en) | Treatment of airway smooth muscle dysfunction | |
Kimoto et al. | A new, simple method for measuring mucociliary clearance in guinea-pigs | |
WO2004004773A1 (en) | Remedies for respiratory diseases | |
US20170020838A1 (en) | Treatment for respiratory disease | |
J. Boots et al. | Respiratory Burns: A Clinical Review | |
CHAN et al. | Plastic bronchitis with life-threatening respiratory failure: a case report | |
Hop et al. | Recombinant human deoxyribonuclease for the treatment of acute asthma in children Ruben Boogaard1, Frank Smit2, Ruud Schornagel3, Anja APH Vaessen-Verberne4, Jan M. Kouwenberg5, Marion Hekkelaan6, Tom Hendriks7, Sander WW Feith8, Wim |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20090625 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20100218 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REF | Corresponds to: |
Ref document number: 602008006024 Country of ref document: DE Date of ref document: 20110519 Kind code of ref document: P |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602008006024 Country of ref document: DE Effective date: 20110519 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: VDEP Effective date: 20110406 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
LTIE | Lt: invalidation of european patent or patent extension |
Effective date: 20110406 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110706 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110808 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110717 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110806 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: BE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110707 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
26N | No opposition filed |
Effective date: 20120110 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602008006024 Country of ref document: DE Effective date: 20120110 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120131 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120131 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120131 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120107 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110706 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120107 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20080107 Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20110406 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 9 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 10 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20191128 Year of fee payment: 13 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20191128 Year of fee payment: 13 Ref country code: DE Payment date: 20200130 Year of fee payment: 13 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R119 Ref document number: 602008006024 Country of ref document: DE |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20210107 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20210131 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20210803 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20210107 |